Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto

Abstract

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the prophylaxis or treatment of platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or a symptom, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders and the like. The present invention also relates to the method of prophylaxis or treatment of 5-HT 2A serotonin receptor mediated disorders in combination with a dopamine D2 receptor antagonist such as haloperidol, administered separately or together.

1 .- 54 . (canceled) 
     
     
         55 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof; 
         wherein: 
         R 1  is aryl or heteroaryl each optionally substituted with R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  each selected independently from the group consisting of C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-6  dialkylamino, C 1-6  alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, C 2-8  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl, or two adjacent R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  together with the atoms to which they are attached form a C 5-7  cycloalkyl group or heterocyclic group each optionally substituted with F, Cl, or Br; and wherein said C 2-6  alkenyl, C 1-6  alkyl, C 2-6  alkynyl, C 1-6  alkylamino, C 1-6  alkylimino, C 2-8  dialkylamino, heterocyclic, and phenyl are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, thiol and nitro; 
         R 2  is selected from the group consisting of H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl and C 3-7  cycloalkyl; 
         R 3  is selected from the group consisting of H, C 2-6  alkenyl, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C 2-6  alkenyl, C 1-6  alkyl, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 3-7  cycloalkyl, heteroaryl and phenyl groups can be optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-5  acyl, C 1-5  acyloxy, C 2-6  alkenyl, C 1-4  alkoxy, C 1-8  alkyl, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-4  alkylcarboxamide, C 2-6  alkynyl, C 1-4  alkylsulfonamide, C 1-4  alkylsulfinyl, C 1-4  alkylsulfonyl, C 1-4  alkylthio, C 1-4  alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6  cycloalkyl, C 2-6  dialkylcarboxamide, halogen, C 1-4  haloalkoxy, C 1-4  haloalkyl, C 1-4  haloalkylsulfinyl, C 1-4  haloalkylsulfonyl, C 1-4  haloalkylthio, hydroxyl, nitro and sulfonamide; 
         R 4  is selected from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, C 2-8  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; 
         R 5  is selected from the group consisting of C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, C 2-8  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, thiol, nitro and sulfonamide, wherein said C 1-6  alkoxy group is optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-5  acyl, C 1-5  acyloxy, C 2-6  alkenyl, C 1-4  alkoxy, C 1-8  alkyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, C 1-4  alkylcarboxamide, C 2-6  alkynyl, C 1-4  alkylsulfonamide, C 1-4  alkylsulfinyl, C 1-4  alkylsulfonyl, C 1-4  alkylthio, C 1-4  alkylureyl, amino, carbo-C 1-6  alkoxy, carboxamide, carboxy, cyano, C 3-6  cycloalkyl, C 2-6  dialkylcarboxamide, halogen, C 1-4  haloalkoxy, C 1-4  haloalkyl, C 1-4  haloalkylsulfinyl, C 1-4  haloalkylsulfonyl, C 1-4  haloalkylthio, hydroxyl, nitro and phenyl, and wherein said amino and phenyl substituents are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C 1-6 -alkoxy; 
         R 6a , R 6b , and R 6c  are each independently selected from the group consisting of H, C 1-6  acyl, C 1-6  acyloxy, C 2-6  alkenyl, C 1-6  alkoxy, C 1-6  alkyl, C 1-6  alkylcarboxamide, C 2-6  alkynyl, C 1-6  alkylsulfonamide, C 1-6  alkylsulfinyl, C 1-6  alkylsulfonyl, C 1-6  alkylthio, C 1-6  alkylureyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7  cycloalkyl, C 2-8  dialkylcarboxamide, C 2-8  dialkylsulfonamide, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, C 1-6  haloalkylsulfinyl, C 1-6  haloalkylsulfonyl, C 1-6  haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; 
         R 7  and R 8  are independently H or C 1-8  alkyl; 
         X is O or S; and 
         Q is C 1-3  alkylene optionally substituted with 1 to 4 substituents selected from the group consisting of C 1-3  alkyl, C 1-4  alkoxy, carboxy, cyano, C 1-3  haloalkyl, halogen and oxo; or Q is a bond; and 
         a pharmaceutically acceptable carrier. 
       
     
     
         56 . The pharmaceutical composition of claim  1 , wherein the therapeutically effective amount is from about 0.001 milligram to about 5,000 milligrams. 
     
     
         57 . The pharmaceutical composition of claim  1 , wherein the therapeutically effective amount is from about 0.001 milligrams to 100 milligrams. 
     
     
         58 . The pharmaceutical composition of claim  1 , wherein the pharmaceutical composition is formulated for a mode of administration selected from the group consisting of oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal, parenteral (including intramuscular, sub-cutaneous and intravenous), inhalation, insufflation, and transdermally. 
     
     
         59 . The pharmaceutical composition of claim  1 , wherein the pharmaceutical composition is administered in a unit dose selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, elixirs, gels, suppositories, sterile injectable solutions, and transdermal patches. 
     
     
         60 . The pharmaceutical composition of claim  1 , wherein the pharmaceutically acceptable salt is selected from the group of acid addition salts consisting of acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, and p-toluenesulfonic. 
     
     
         61 . The pharmaceutical composition of claim  1 , wherein the compound of Formula I is administered in combination with a dopamine D2 receptor antagonist. 
     
     
         62 . The pharmaceutical composition of  claim 61 , wherein the dopamine D2 receptor antagonist is Haloperidol. 
     
     
         63 . The pharmaceutical composition of  claim 61 , wherein the compound of Formula I and the dopamine D2 receptor antagonist are administered separately or together. 
     
     
         64 . The pharmaceutical composition of  claim 61 , wherein the combination of the compound of Formula I and the dopamine D2 receptor antagonist is used to treat a disorder selected from the group consisting of behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, psychosis, psychotic disorder, schizophrenia, infantile autism, huntington's chorea, and nausea or vomiting resulting from chemotherapy. 
     
     
         65 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ha): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate or solvate thereof; 
         wherein: 
         R 1  is phenyl or naphthyl optionally substituted with R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  each selected independently from the group consisting of C 1-6  acyl, C 1-6  alkoxy, C 1-6  alkyl, amino, C 1-6  alkylamino, C 2-6  dialkylamino, C 1-6  alkylimino, cyano, halogen, C 1-6  haloalkoxy, C 1-6 haloalkyl, heterocyclic, hydroxyl, nitro, and phenyl, or two adjacent R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  together with the atoms to which they are attached form a C 5-7  cycloalkyl group or heterocyclic group each optionally substituted with F; and wherein said C 1-6  alkyl, C 1-6  alkylimino, and heterocyclic are each optionally substituted with 1 to 5 substituents selected independently from the group consisting of C 1-6  alkyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, and hydroxyl; 
         R 2  is C 1-6  alkyl; 
         R 3  is H or halogen; 
         R 4  is selected from the group consisting of H, C 1-6  alkyl and C 1-6  haloalkyl; 
         R 5  is selected from the group consisting of C 1-6  alkoxy, C 1-6  haloalkoxy, and hydroxyl, wherein said C 1-6 alkoxy group can be optionally substituted with 1 to 5 further substituents selected independently from the group consisting of amino, C 2-8  dialkylamino, carboxy, and phenyl, and wherein said amino and phenyl are each optionally substituted with 1 to 5 further substituents selected from the group consisting of halogen and carbo-C 1-6  alkoxy; 
         R 6a , R 6b , and R 6c  are each independently selected from the group consisting of H, C 1-6  alkoxy, C 1-6  alkyl, amino, C 1-6  alkylamino, C 2-8  dialkylamino, cyano, halogen, C 1-6  haloalkoxy, C 1-6  haloalkyl, hydroxyl, and nitro; 
         R 7  and R 8  are both H; 
         X is O; and 
         Q is a bond; and 
         a pharmaceutically acceptable carrier. 
       
     
     
         66 . The pharmaceutical composition of  claim 65 , wherein the therapeutically effective amount is from about 0.001 milligram to about 5,000 milligrams. 
     
     
         67 . The pharmaceutical composition of  claim 65 , wherein the therapeutically effective amount is from about 0.001 milligrams to about 100 milligrams. 
     
     
         68 . The pharmaceutical composition of  claim 65 , wherein the pharmaceutical composition is formulated for a mode of administration selected from the group consisting of oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal, parenteral (including intramuscular, sub-cutaneous and intravenous), inhalation, insufflation, and transdermally. 
     
     
         69 . The pharmaceutical composition of  claim 65 , wherein the pharmaceutical composition is administered in a unit dose selected from the group consisting of tablets, capsules, solutions, suspensions, emulsions, elixirs, gels, suppositories, sterile injectable solutions, and transdermal patches. 
     
     
         70 . The pharmaceutical composition of  claim 65 , wherein the pharmaceutically acceptable salt is selected from the group of acid addition salts consisting of acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, and p-toluenesulfonic. 
     
     
         71 . The pharmaceutical composition of  claim 65 , wherein the compound of Formula IIa is administered in combination with a dopamine D2 receptor antagonist. 
     
     
         72 . The pharmaceutical composition of  claim 71 , wherein the dopamine D2 receptor antagonist is Haloperidol. 
     
     
         73 . The pharmaceutical composition of  claim 71 , wherein the compound of Formula IIa and the dopamine D2 receptor antagonist are administered separately or together. 
     
     
         74 . The pharmaceutical composition of  claim 71 , wherein the combination of the compound of Formula Ha and the dopamine D2 receptor antagonist is used to treat a disorder selected from the group consisting of behavioral disorder, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, psychosis, psychotic disorder, schizophrenia, infantile autism, huntington's chorea, and nausea or vomiting resulting from chemotherapy.